Compelling evidence suggests that current structural models of epidermal growth factor receptor (EGFR) signaling are incomplete, as they cannot account for the population of inactive, pre-assembled receptor dimers in cells that exhibit negatively cooperative ligand binding. Thus, rather than proceeding through simple ligand- induced dimerization, EGFR signaling involves the ligand-dependent allosteric regulation of receptor dimers. This proposal describes how I will (i) obtain a thorough structural understanding of pre-assembled EGFR dimers, (ii) identify the conformational changes that switch receptor dimers between the 'off' and 'on' states, and (iii) investigate the much-discussed possibilities of oncogenic mutation- and ligand-specific 'on' states of EGFR that differentially modulate signaling output. My preliminary data shows that the highly-homologous C. elegans EGFR is constitutively dimeric, which circumvents technical challenges associated with human EGFR and provides a unique and straightforward opportunity to answer these important mechanistic questions. Since excessive EGFR signaling drives many human cancers, the results will provide the conceptual framework for designing a new generation of 'smarter' EGFR-targeted cancer therapies.